EP1379523B1 - 1,2,3,4-tetrahydroisoquinolines derivatives as urotensin ii receptor antagonists - Google Patents

1,2,3,4-tetrahydroisoquinolines derivatives as urotensin ii receptor antagonists Download PDF

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EP1379523B1
EP1379523B1 EP02730036A EP02730036A EP1379523B1 EP 1379523 B1 EP1379523 B1 EP 1379523B1 EP 02730036 A EP02730036 A EP 02730036A EP 02730036 A EP02730036 A EP 02730036A EP 1379523 B1 EP1379523 B1 EP 1379523B1
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dimethoxy
ethyl
isoquinolin
dihydro
urea
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French (fr)
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EP1379523A1 (en
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Hamed Aissaoui
Christoph Binkert
Martine Clozel
Boris Mathys
Claus Mueller
Oliver Nayler
Michael Scherz
Thomas Weller
Jörg Velker
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Actelion Pharmaceuticals Ltd
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Definitions

  • the present invention relates to novel 1,2,3,4-tetrahydroisoquinoline derivatives of the general formula 1 and their use as active ingredients in the preparation of pharmaceutical compositions.
  • the invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of the general formula 1 and especially their use as neurohormonal antagonists.
  • Urotensin II is a cyclic 11-amino acid peptide that has some sequence similarity to, but is not homologous with, somatostatin-14. Urotensin II was first isolated and sequenced from fish spinal cord (Bern HA, Pearson D, Larson BA, Nishioka RS. Neurohormones from fish tails: the caudal neurosecretory system. I. "Urophysiology” and the caudal neurosecretory system of fishes. Recent Prog. Horm. Res. (1985) 41, 533-552), and has since been found in a wide variety of vertebrate and invertebrate species.
  • Human urotensin II is synthesized in a prepro-form from a single gene located at chromosome 1p36.21. and two cDNA splice variants which differ in their putative signal peptide sequence have been isolated from human colon tumor and human placenta (GenBank Accession Nr. 095399).
  • the putative prohormone convertase dibasic cleavage site is strictly conserved across species.
  • the mature 11-amino acid peptide contains a C-terminal disulfide-bridged 6-amino acid loop which is also strictly conserved, while the N-terminal portion of the mature cyclic peptide can vary considerably across species.
  • Urotensin II exerts potent and complex hemodynamic actions in mammals (Douglas SA, Sulpizio AC, Piercy V, Sarau HM, Ames RS, Aiyar NV, Ohlstein EH, Willette RN. "Differential vasoconstrictor activity of human urotensin-II in vascular tissue isolated from the rat, mouse, dog, pig, marmoset and cynomolgus monkey.” Br. J. Pharmacol. (2000) 131, 1262-1274.
  • GPR14 G-protein-coupled orphan receptor
  • urotensin II potently affects atrial and ventricular muscle contraction (Russell FD, Molenaar P, and O'Brien DM "Cardiostimulant effects of urotensin-II in human heart in vitro". Br J Pharmacol (2001) 132, 5-9).
  • Urotensin II stimulates cellular proliferation, migration and collagen synthesis in cardiac fibroblasts (Tzandis A, et al., "Urotensin II stimulates collagen synthesis by cardiac fibroblasts and hypertrophic signaling cardiomyocytes via G(alpha)q- and Ras-dependent pathways”. J. Am. Coll. Cardiol. (2001) 37, 164A.) and in neonatal myocytes (Zou Y, Nagai R, and Yamazaki T, "Urotensin II induces hypertrophic responses in cultured cardiomyocytes from neonatal rats". FEBS Lett (2001) 508, 57-60). Urotensin II is produced by cancer cell lines and its receptor is also expressed in these cells.
  • Urotensin II modulates glucose-stimulated pancreatic release of insulin (Silvestre RA, et al., "Inhibition of insulin release by urotensin II-a study on the perfused rat pancreas. Horm Metab Res (2001) 33, 379-81).
  • Elevated circulating levels of urotensin II are detected in humans susceptible to high-altitude pulmonary edema, and in patients awaiting kidney transplantation (Totsune K, et al., "Role of urotensin II in patients on dialysis”. Lancet (2001) 358, 810-1).
  • Urotensin II and its receptor are found in spinal cord and brain tissue, and intracerebroventricular infusion of urotensin II into mice induces behavioral changes (Gartlon J, et al., "Central effects of urotensin-II following ICV administration in rats”. Psychopharmacology (Berlin) (2001) 155. 426-33).
  • WO-2001/45694 discloses certain sulfonamides as urotensin II receptor antagonists, and their use to treat diseases associated with a urotensin II imbalance.
  • WO-2001/45700 discloses certain pyrrolidines as urotensin II receptor antagonists and their use to treat diseases associated with a urotensin II imbalance.
  • WO-2001/45711 discloses certain pyrrolyl and pyridyl derivatives as urotensin II receptor antagonists and their use to treat diseases associated with a urotensin II imbalance.
  • WO-2002/00606 discloses certain biphenyl compounds useful as urotensin II receptor antagonists, and WO-2002/02530 also discloses certain compounds useful as urotensin II receptor antagonists.
  • the present invention comprises 1,2,3,4-tetrahydroisoquinoline derivatives which are novel compositions of matter and which are urotensin II receptor antagonists.
  • EP 0 501 693 discloses also 1,2,3,4-tetrahydroisoquinoline derivatives but with a different substitution pattern especially at the ring nitrogen and these compounds apparently do not exhibit any urotensin II antagonistic activity.
  • the present invention relates to compounds of the general formula 1, wherein
  • C1-C4 alkyl means straight or branched chain groups with one to four carbon atoms; or cyclic alkyl groups with three to six carbon atoms.
  • Preferred examples of C1-C4 alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • 'C1-C4 alkyloxy' means a group of the formula C1-C4 alkyl-O- in which the term 'C1-C4 alkyl' has the meaning previously given.
  • Preferred examples of lower alkyloxy groups are methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, sec-butoxy, tert-butoxy, cyclopentyloxy, and cyclohexyloxy.
  • 'C2-C5 alkenyloxy' means a group of the formula C2-C5 alkenyl-O- in which the term 'C2-C5 alkenyl' means a straight-chain or branched-chain alkenyl group with 2 to 5 carbon atoms.
  • Preferred examples of lower alkenyloxy groups are allyloxy or propenyloxy.
  • aryl' means a phenyl or naphthyl group which optionally carries one or more substituents, preferably one or two substituents, each independently selected from cyano, halogen, C1-C4 alkyl, C2-C5 alkenyl, C1-C4 alkyloxy, C2-C5 alkenyloxy, trifluoromethyl, trifluoromethoxy, amino, carboxy and the like.
  • aryl groups are phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-cyanophenyl, 4-chlorophenyl, 4-fluorophenyl, 2-methylphenyl, 2-chlorophenyl, 2-fluorophenyl, 2-methoxyphenyl, naphthalen-1-yl and naphthalen-2-yl.
  • 'aralkyl' means a C1-C4 alkyl group as previously defined in which one hydrogen atom has been replaced by an aryl group as previously defined.
  • Preferred examples of aralkyl groups are benzyl and benzyl substituted in the phenyl ring with hydroxy, C1-C4 alkyl, C1-C4 alkyloxy or halogen.
  • 'aralkyloxy' means a group of the formula aralkyl-O- in which the term 'aralkyl' has the meaning previously given.
  • Preferred examples of aralkyloxy are benzyloxy and phenethyloxy.
  • the present invention encompasses pharmaceutically acceptable salts of compounds of the general formula 1.
  • This encompasses either salts with inorganic acids or organic acids like hydrohalogenic acids, e.g. hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, citric acid, formic acid, acetic acid, maleic acid, tartaric acid, methylsulfonic acid, p- tolylsulfonic acid and the like or in case the compound of formula 1 is acidic in nature with an inorganic base like an alkali or earth alkali base, e.g. sodium, potassium, or calcium salts, etc.
  • the present invention encompasses different solvation complexes of compounds of general formula 1.
  • the solvation can be effected in the course of the manufacturing process or can take place separately, e.g. as a consequence of hygroscopic properties of an initially anhydrous compound of general formula 1.
  • the present invention further encompasses different morphological forms, e.g. crystalline forms, of compounds of general formula 1 and their salts and solvation complexes. Particular heteromorphs may exhibit different dissolution properties, stability profiles, and the like, and are all included in the scope of the present invention.
  • the compounds of the general formula 1 might have one or more asymmetric carbon atoms and may be prepared in form of optically pure enantiomers or diastereomers, mixtures of enantiomers or diastereomers, diastereomeric racemates, and mixtures of diastereomeric racemates.
  • the present invention encompasses all these forms. They are prepared by stereoselective synthesis, or by separation of mixtures in a manner known per se, i.e. by column chromatography, thin layer chromatography, HPLC, crystallization, etc.
  • Preferred compounds of general formula 1 are the compounds of general formula 2, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, Z, and n have the meaning given in general formula 1 above.
  • Another group of preferred compounds of general formula 1 are the compounds of general formula 3, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, Y, and Z have the meaning given in general formula 1 above.
  • Another group of preferred compounds of general formula 1 are the compounds of general formula 4, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Y, Z, and n have the meaning given in general formula 1 above.
  • Another group of preferred compounds of general formula 1 are the compounds of general formula 5, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Y, Z, and n have the meaning given in general formula 1 above.
  • Another group of preferred compounds of general formula 1 are the compounds of general formula 6, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Y, Z, and n have the meaning given in general formula 1 above.
  • Another group of preferred compounds of general formula 1 are the compounds of general formula 7, wherein R 1 , R 3 , R 4 , R 5 , R 6 , X, Y, Z, and n have the meaning given in general formula 1 above.
  • Another group of preferred compounds of general formula 1 are the compounds of general formula 8, wherein Ph is phenyl; mono-, di- or tri-substituted phenyl, substituted independently with hydrogen, C1-C4 alkyl, C1-C4 alkyloxy, trifluoromethyl, halogen, or cyano; and R 3 , R 4 , R 5 , R 6 , X, Y, Z, and n have the meaning given in general formula 1 above.
  • Another group of preferred compounds of general formula 1 are the compounds of general formula 9, wherein R 1 , R 2 , X, Y, Z, and n have the meaning given in general formula 1 above.
  • Another group of preferred compounds of general formula 1 are the compounds of general formula 10, wherein R 1 , R 2 . X, Y, Z, and n have the meaning given in general formula 1 above.
  • Another group of preferred compounds of general formula 1 are the compounds of general formula 11, wherein R 1 , R 2 , X, Y, Z, and n have the meaning given in general formula 1 above.
  • Another group of preferred compounds of general formula 1 are the compounds of general formula 12, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, Y, and n have the meaning given in general formula 1.
  • Another group of preferred compounds of general formula 1 are the compounds : of general formula 13, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, Y, and n have the meaning given in general formula 1.
  • Another group of preferred compounds of general formula 1 are the compounds of general formula 14, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X, Y, and n have the meaning given in general formula 1.
  • Another group of preferred compounds of general formula 1 are the compounds of general formula 15, wherein the 1 position of the 1,2,3,4-tetrahydroisoquinoline ring system has the R absolute stereochemical configuration, and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, Z, and n have the meaning given in general formula 1.
  • R 3 , R 4 , R 5 , and R 6 are independently hydrogen or C1-C4 alkyloxy; and R 1 , R 2 , and Z have the meaning given in general formula 1 above.
  • the described compounds can be used for treatment of diseases which are associated with an increase in vasoconstriction, proliferation or other disease states associated with the actions of urotensin II.
  • diseases are hypertension, atherosclerosis, angina or myocardial ischemia, congestive heart failure, cardiac insufficiency, cardiac arrhythmias, renal ischemia, chronic kidney disease, renal failure, stroke, cerebral vasospasm, cerebral ischemia, dementia, migraine, subarachnoidal hemorrhage, diabetes, diabetic arteriopathy, asthma, chronic obstructive pulmonary disease, high-altitude pulmonary edema, Raynaud's syndrome, portal hypertension, thyroid dysfunction, pulmonary edema, pulmonary hypertension, or pulmonary fibrosis.
  • They can also be used for prevention of restenosis after balloon or stent angioplasty, cancer, prostatic hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma, gram negative septicemia, shock, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, therapy and prophylaxis of diabetic complications, : complications of vascular or cardiac surgery or after organ transplantation, complications of cyclosporin treatment, pain, addictions, schizophrenia, .
  • Alzheimer's disease anxiety, obsessive-compulsive behavior, epileptic seizures, stress, depression, dementias, neuromuscular disorders, neurodegenerative diseases, as well as other diseases related to a dysregulation of urotensin II or urotensin II receptors.
  • compositions may be administered in enteral or oral form e.g. as tablets, dragees, gelatine capsules, emulsions, solutions or suspensions, in nasal form like sprays or rectally in form of suppositories.
  • enteral or oral form e.g. as tablets, dragees, gelatine capsules, emulsions, solutions or suspensions, in nasal form like sprays or rectally in form of suppositories.
  • These compounds may also be administered in intramuscular, parenteral or intravenous form, e.g. in form of injectable solutions.
  • compositions may contain the compounds of formula 1 as well as their pharmaceutically acceptable salts in combination with inorganic and/or organic excipients, which are usual in the pharmaceutical industry, like lactose, maize or derivatives thereof, talcum, stearic acid or salts of these materials.
  • vegetable oils, waxes, fats, liquid or half-liquid polyols etc. may be used.
  • solutions and sirups e.g. water, polyols, saccharose, glucose etc. are used.
  • injectables are prepared by using e.g. water, polyols, alcohols, glycerin, vegetable oils, lecithin, liposomes etc.
  • Suppositories are prepared by using natural or hydrogenated oils, waxes, fatty acids (fats), liquid or half-liquid polyols etc.
  • compositions may contain in addition preservatives, stabilisation improving substances, viscosity improving or regulating substances, solubility improving substances, sweeteners, dyes, taste improving compounds, salts to change the osmotic pressure, buffer, anti-oxidants etc.
  • the compounds of general formula 1 may also be used in combination with one or more other therapeutically useful substances e.g. ⁇ - and ⁇ -blockers like phentolamine, phenoxybenzamine, atenolol, propranolol, timolol, metoprolol, carteolol, carvedilol, etc.; with vasodilators like hydralazine, minoxidil, diazoxide, flosequinan, etc.; with calcium-antagonists like diltiazem, nicardipine, nimodipine, verapamil, nifedipine, etc.; with angiotensin converting enzyme-inhibitors like cilazapril, captopril, enalapril, lisinopril etc.; with potassium channel activators like pinacidil, chromakalim, etc.; with angiotensin receptor antagonists like losartan, valsartan, can
  • the dosage may vary within wide limits but should be adapted to the specific situation.
  • the dosage given daily in oral form should be between about 3 mg and about 3 g, preferably between about 10 mg and about 1 g, especially preferred between 5 mg and 300 mg, per adult with a body weight of about 70 kg.
  • the dosage should be administered preferably in 1 to 3 doses of equal weight per day. As usual children should receive lower doses which are adapted to body weight and age.
  • 1,2,3,4-Tetrahydroisoquinolines and 1,2,3,4-tetrahydrobenz[c]azepines of general structure I in Schemes A through C are either commercially available or are prepared in racemic or optically active form by methods well known in the art.
  • they can be prepared by a ring-closing condensation reaction of amides derived from the corresponding phenylethylamines or phenylpropylamines and the appropriate carboxylic acid under the action of POCl 3 or PCl 5 , followed by treatment with a reducing agent such as NaBH 4 (Whaley WM, Govindachari TR "The preparation of 3,4-dihydroisoquinolines and related compounds by the Bischler-Napieralski reaction.” Org. React. (1951) 6, 74-106.
  • a reducing agent such as NaBH 4
  • the key step of this asymmetric synthesis is a stereoselective hydride reduction of a chiral iminium ion obtained by Bischler-Napieralski reaction.
  • the chirality resident in the substrate is derived from commercially available ( R )-(+)- ⁇ -phenethylamine .
  • Reactions are routinely performed under an inert atmosphere such as N 2 gas in air dried glassware. Solvents are used as received from the vendor. Evaporations are performed in a rotary evaporator at reduced pressure and a water bath temperature of 50°C. LC-MS characterizations are performed on a Finnigan HP1100 platform using ESI ionization mode, and positive ion detection with a Navigator AQA detector. Analytical liquid chromatographic separations are performed on a C18 column of 4.6 x 30 mm dimensions and a mobile phase consisting of a 6 minute gradient of 2 - 95% CH 3 CN in water containing 0.5% formic acid at a flow rate of 0.45 mL/min. Retention time (t R ) is given in min. TLC is performed on pre-coated silica gel 60 F 254 glass-backed plates (Merck).
  • Preparative HPLC is performed on a Varian/Gilson platform using a C18 column of 21 x 60 mm dimensions and a mobile phase consisting of a gradient of 2 - 95% CH 3 CN in water containing 0.5% formic acid.
  • reaction mixture is concentrated in vacuo, extracted three times with CH 2 Cl 2 and the combined organic extracts are washed with saturated aqueous NaHCO 3 and brine.
  • organic phase is dried over anhydrous MgSO 4 , filtered and concentrated to give the title compound as a colorless solid.
  • the compound is prepared from 3-(2,3-difluoro-phenyl)-propionic acid and 2-(3,4-dimethoxy-phenyl)-ethylamine according to the method of example A8.
  • a stirred suspension of LAH (8.0 g, 0.21 mol) in THF (300 mL) is cooled in an ice bath and a solution of 4-benzyloxy-3-methoxynitrostyrene (15.0 g, 52.6 mmol) in THF (300 mL) is added dropwise.
  • the green reaction mixture is allowed to warm to room temperature over 0.5 h, and is then refluxed for 4 h.
  • the grey reaction mixture is treated successively with water (8 mL), 15% aqueous NaOH (8 mL), and water (24 mL).
  • the resulting gray suspension is stirred at 50 °C for 20 min.
  • the resulting yellow suspension is filtered, and the residue is washed with EtOAc.
  • the combined filtrates are evaporated to provide the title compound as yellow oil which is used without further purification.
  • the aqueous phase is extracted with CH 2 Cl 2 (2 x 100 mL), and the combined organic phases are dried (MgSO4), filtered and evaporated to provide the title compound as yellow oil. Purification is achieved by crystallization from MeOH. The evaporated mother liquor furnishes additional material, upon silica gel chromatography (heptane:Et2O, 9:1).
  • Tetrakis-(triphenylphosphine)-palladium (1.0 g) is added, and the brown reaction, mixture is stirred at 120 °C for 2 h.
  • the reaction mixture is cooled to rt, and partitioned between EtOAc and saturated aqueous NaHCO 3 .
  • the mixture is filtered through Hyflo.
  • the aqueous phase is extracted with EtOAc (3 x 40 mL).
  • the combined organic phases are extracted with brine, dried over MgSO 4 , filtered, and evaporated.
  • the resulting yellow oil partially solidifies.
  • the mixture is filtered and washed with Et 2 O to provide the title compound as white crystals. Evaporation of the filtrate and silica gel chromatography (EtOAc:heptane, 1:4) provides additional title compound as white crystals.
  • the fine yellow suspension is diluted with CH 2 Cl 2 (10 mL), and is washed with 1 M aqueous HCl and saturated aqueous NaHCO 3 .
  • the organic phase is dried over MgSO 4 , filtered and evaporated to give the title compound.
  • Enantiomerically pure starting materials are prepared according to the method of Polniaszek R.P. et al., J. Am. Chem. Soc. (1989) 111, 4859-4863.
  • This material is prepared analogously to example B1 from 3-chloropropylamine.
  • This material is commercially available.
  • This material is commercially available.
  • This material is commercially available.
  • This material is prepared by reaction of isatin with acetone according to the method described in Brasyunas VB et al., "Synthesis of Quinoline-4-car,boxylic acid and its derivatives", Chem. Heterocycl. Compd. (engl. Transl.) (1988) 670-673.
  • This material is prepared by reaction of 2-chloro-6-methyl-pyridine-4-carboxylic acid with benrylmethylamine analogously to example C8.
  • This material is prepared by reaction of 2-chloro-pyridine-4-carboxylic acid with N-methylaniline analogously to example C8.
  • This material is prepared by reaction of 2-chloro-pyridine-4-carboxylic acid with pyrrolidine analogously to example C8.
  • the title compound is prepared from 4-amino-7-methyl-[1,8]-naphthyridine (example C5) and 2-chloroethylisocyanate.
  • the assay is performed in 250 ⁇ L Dubecco's modified eagle medium, pH 7.4 (GIBCO BRL, CatNo 31885-023), including 25 mM HEPES (Fluka, CatNo 05473), 1.0 % DMSO (Fluka, CatNo 41644) and 0.5% (w/v) BSA Fraction V (Fluka, CatNo 05473) in polypropylene microtiter plates (Nunc, CatNo 442587). 300'000 suspended cells are incubated with gentle shaking for 4 h at 20°C with 20 pM human [1251]Urotensin II (Anawa Trading SA, Wangen, Switzerland, 213OCi/mmol) and increasing concentrations of unlabeled antagonist.
  • Minimum and maximum binding are derived from samples with and without 100 nM unlabelled U-II, respectively.
  • the cells are filtered onto GF/C filterplates (Packard, CatNo 6005174).
  • the filter plates are dried, and then 50 ⁇ L scintillation cocktail (Packard, MicroScint 20, CatNo 6013621) is added to each well.
  • the filterplates are counted in a microplate counter (Packard Bioscience, TopCount NXT).
  • IC50 values are defined as the concentration of antagonist inhibiting 50% of the specific binding of [ 125 1]human U-II. Specific binding is the difference between maximum binding and minimum binding, as described above. An IC50 value of 0.206 nM is found for unlabeled human U-II.
  • the compounds of the invention are found to have IC50 values ranging from 1 to 10000 nM in this assay. Specific examples have IC50's given in the following table.
  • the rings are stretched to a resting tension of 3g. Cumulative doses of human urotensin II (10 -11 M to 10 -6 M) are added after a 20 min incubation with the test compound or its vehicle (DMSO, 10 ⁇ L). An EC50 value of 1.09 ⁇ 0.1 nM is found for unlabeled human U-II.

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EP02730036A 2001-03-27 2002-03-20 1,2,3,4-tetrahydroisoquinolines derivatives as urotensin ii receptor antagonists Expired - Lifetime EP1379523B1 (en)

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